Sedative tablet and method for producing the same



United States Patent 3,198,700 SEDATIVE TABLET AND NETHGD FDR PRODUCING THE SAD E Stanley S. Sidenberg, University Heights, Cleveland, and Frederick J. Bandelin, Lyndhurst, Ohio, assignors to Blessings, Inc., Cleveland, Ohio, a corporation of Ohio No Drawing. Filed May 29, 1961, Ser. No. 113,095 9 Claims. (Cl. 16752) This invention relates to pharmaceutical compositions and more particularly to chloral hydrate, and method and means of stabilizing chloral hydrate for solid dosage use and use with other therapeutic substances.

Chloral hydrate (2,2,2 trichloro 1,1 ethanediol, C H Cl 0 has long been known as an effective sedative, hypnotic and anti-convulsant. It is extremely soluble inwater, hygroscopic, volatile and sublimates on'exposure to air. It has a pungent odor and taste and is toxic if taken in sufiiciently large doses. Chloral hydrate has a boiling point of 98 C. with disassociation into water and chloral. It is also soluble in alcohols. Because of its value as a sedative, on the one hand, its toxicity, when taken in too large doses, and instability, on the other hand, there has been a long recognized need for providing chloral hydrate in a stable solid dosage form, such as a tablet, so that the quality and strength of dosage is properly controlled and properly and easily administered for and by the user even though untrained.

Difiiculty has been experienced in providing a solid dosage form of chloral hydrate, such as a tablet. This is because chloral hydrate sublimes, is extremely soluble, hygroscopic and volatile, and has a marked tendency to bleed through coatings such as are usually used in the manufacture of tablets for medicinal purposes.

Consequently, chloral hydrate has conventionally been sold as a powder for dissolving in a liquid just prior to use or as an oil capsule, which, nevertheless, bleeds after a relatively short period of time.

The general object of this invention is therefore to provide a stable, solid dosage form of chloral hydrate.

Further objects of this invention include the provision of a solid dosage chloral hydrate tablet which is stable; which has a long shelf life; which is non-hygroscopic; which does not bleed through coatings usually used in the manufacture of tablets for medicinal purposes; which does not lose its potency by evaporation or sublimation even when retained for extended periods of time; which does not adversely affect the normal sedative and anticonvulsant properties and characteristics of the chloral hydrate; and, which reduces the toxicity of the chloral hydrate.

Still further objects of this invention include the provision of a tablet combining, in stable form, both a slow acting, long lasting sedative and quick acting, short lasting sedative and the provision of method and means for providing such a tablet.

Other objects of this invention include the provision of method and means for providing stable choral hydrate in solid dosage form; the provision of a stable chloral hydrate tablet; and, the provision of method and means whereby compressed tablets of chloral hydrate can be sugar coated by usual methods.

Still further objects of this invention include the provision of a sedative tablet having a core of stabilized chloral hydrate and a coating including a barbiturate, or other therapeutic substance; the provision of a solid dosage tablet of chloral hydrate and glycine; the provision of chloral hydrate in a stable tablet, also comprising one or more other therapeutic substances, and the provision of method and means for providing such tablets.

A still further object of this invention is to provide a stable chloral hydrate tablet and method and means for producing the same obtaining and having one or more of the objects and advantages set forth above.

These and other objects and advantages of this invention will appear from the following description of a preferred and modified form thereof.

Broadly, this invention comprises the provision of a stable, solid dosage, chloral hydrate tablet comprising a core mixture of chloral hydrate (2,2,2 trichloro 1,1- ethanediol, C H Cl O and glycine (amino acetic acid, NH CH COOH) which buffers the normal properties and characteristics of the chloral hydrate so that the same, as a part of the core mixture, may be and is coated in accordance with usual practice or, in the preferred embodim nt of this invention, with a new and improved coating including another therapeutic substance. Preferably the new coating includes a quick acting, short lasting sedative, such as a barbiturate, to provide a tablet comprising both a slow acting, long lasting and a quick acting, short lasting sedative. This invention also comprises the provision of a process for obtaining stable, solid dosage chloral hydrate, as in a tablet, and a process for obtaining a sedative tablet having both a quick acting, short lasting and slow acting, long lasting sedative.

More particularly, a tablet embodying this invention comprises from, at least, 0.8 part by weight of glycine (amino acetic acid, NH CH COOH) to one part of chloral hydrate and preferably contains 1.37 parts by weight of glycine to one part of chloral hydrate.

In accordance with the preferred form of this invention stable, solid dosage chloral hydrate is prepared from chloral hydrate and glycine by moistening the same with a suitable vehicle and mixing together preferably with a binder. A ten percent solution of polyvinylpyrrolidone in water is preferably used to moisten the chloral hydrate and glycine to facilitate mixture and to bind the ingredients together in the completed tablet. The moist mass thus obtained is passed through a wire screen of suittable mesh and dried in a suitable oven at F. When dried the mass is reduced in size, if desired, by passing through a smaller mesh screen.

The resultant granules are lubricated with 2 percent by weight of magnesium stearate, which may be added prior to or during mixing, if desired, and compressed to a predetermined tablet size. The tablet is then coated in the usual manner with successive coats of mixtures of gelatin, sugar and inert powders and/or shellac.

Example 1 2 lbs., 10 ozs., 375 grs. of chloral hydrate crystals, 3 lbs., 10 02s., 325 grs. of glycine and 1 oz., 413 grs. of magnesium stearate were granulated with a ten percent solution of polyvinylpyrrolidone in water. The resultant mass was dried at 80 F. and compressed into tablets. Each tablet was formed to contain 3.75 grains of chloral hydrate and 5.14 grains of glycine.

Example 2 3 lbs., 9 02s., 62.5 grs. of chloral hydrate crystals, 4 lbs., 14 us, 225 grs. of glycine and 2 ozs., 310 grs. of

a magnesium stearate were granulated with a ten percent solution of polyvinylpyrrolidone in Water. The resultant mass was dried at 80 F. and compressed into tablets. Each tablet was formed to contain 5.0 grains of chloral hydrate and 6.85 grains of glycine.

Example 3 lbs., 5 02s., 312.5 grs. of chloral hydrate crystals, 7 lbs., 5 025., 187.5 grs. of glycine and 4 02s., 27 grs. of magnesium stearate were granulated with a ten percent solution of polyvinylpyrrolidone in water. The resultant.

mass was dried at 80 F. and compressed into tablets. Each tablet was formed to contain 7.5 grains of chloral hydrate and 10.27 grains of glycine.

Alternatively, the magnesium stearate may be added at the time of tablet formation and may be omitted when tablets are not formed, since it functions as a lubricant in a manner well known in the tablet making art and does not otherwise cooperate with the chloral hydrate and glycine to obtain the objects and advantages of this invention. Similarly, the polyvinylpyrrolidone is a binder well known to the tablet making art and does not otherwise cooperate with the chloral hydrate and glycine to obtain the advantages of this invention.

Example 4 The above procedure has also been used to provide stable solid dosage chloral hydrate in tablets having 0.5 gram chloral hydrate and 0.4 gram glycine (ratio of 0.8 part by weight of glycine to 1 part of chloral hydrate).

This invention also comprises providing tablets comprising both chloral hydrate and another therapeutic substance. bodying this invention are coated with a coating having at least one layer which includes the desired second therapeutic substance. Such layer is preferably spaced from the chloral hydrate-glycine core to prevent reaction therewith. Thus, a tablet embodying this invention may comprise both a quick-acting, short-lasting and a slow-acting, long-lasting sedative, by coating the compressed cores of chloral hydrate and glycine with a coating having one or more layers, spaced from the core and including a gelatin solution of a barbiturate, such as secobarbital.

For example, tablets containing a core of 0.5 gram of chloral hydrate and 0.4 gram of glycine were prepared having 0.894 gram of secobarbital in the coating. Both the chloral hydrate and the secobarbital were stable.

Similarly, tablets containing a core of 3.75 grains of chloral hydrate, 5.14 grains of glycine and a coating having a 0.75 grain of butabarbital were prepared. These tablets were also stable.

Either barbiturate may be used in place of the other and other barbiturates or therapeutic substances can be used in the coating if desired, so long as they are compatible with, and not adversely effected by, the substances with which they are in contact.

A tablet embodying this invention is coated, for example, as follows:

(1) Three applications of percent cellulose acetatephthalate in ethanol and dust with magnesium stearate.

(2) Two applications of 10 percent acacia in syrup.

(3) Two applications of shellac-arlacel solution and dust with calcium sulfate.

(4) Three applications of a subcoat of gelatin solution with secobarbital in calcium sulfate.

(5) Two applications of gelatin solution with calcium sulfate.

(6) At least one application of syrup to smooth tablet.

(7) Application of syrup with certified dye to color.

(8) Wax and polish.

In order to provide tablets of convenient size and useful though safe strength, a tablet having a conventional coating conveniently comprises 5 grains of chloral hydrate To this end, chloral hydrate-glycine tablets ema and 6.85 grains of glycine and a tablet having a coating embodying a barbiturate, in accordance with this invention, comprises 3.75 grains of chloral hydrate, 5.14 grains of glycine and 0.75 grain of barbiturate, secobarbital.

Tests by infra red adsorption spectra of tablets embodying this invention and of the component parts indicate that the tablet contains chloral hydrate unchanged.

Further, tablets embodying this invention have been found stable and without deterioration or decomposition of any type after 14 months retention and on an accelerated test after 500 hours of retention at 45 C.

The glycine does not adversely affect the desirable therapeutic effects of the chloral hydrate. On the other hand, tests have shown that the glycine does reduce the toxicity of the chloral hydrate by More particularly, test results showed that the lethal dose necessary to kill 50% (LD of the test animals (mice) was 1.42 grams of chloral hydrate per kilogram of mouse as against 5.82 grams of chloral hydrate-glycine (in the ratio of 1.37 parts of glycine by weight per part of chloral hydrate) per kilogram of mouse, for a single oral dose.

The maximum proportion of glycine to chloral hydrate, once sufiicient glycine is used to obtain the desired stability, is limited more by the necessity of having tablets of reasonable size, which include a useful dose of chloral hydrate. Accordingly, as noted above, stable, solid dosage chloral hydrate ernbodying this invention preferably comprises 1.37 parts by weight of glycine per part of chloral hydrate.

Modifications, changes and improvements to the preferred and modified forms of the invention herein described may occur to those skilled in the art who come to understand the principles and precepts thereof. Ac cordingly, the scope of the patent should not be limited to the specific embodiments of the invention herein described but by the advance by which the invention has promoted the art.

We claim:

1. The process of preparing a stable, solid dosage chloral hydrate tablet comprising the steps of mixing chloral hydrate and glycine, in the proportion of at least 0.8 part by weight of glycine to 1 part by weight of chloral hydrate, moistened by the presence of a liquid vehicle, granulating the mixture, drying the mass at a temperature substantially below the boiling point of chloral hydrate, and compressing the mass into tablets of predetermined size.

2. A stable solid dosage chloral hydrate tablet comprising a coating and a core, said core comprising glycine and chloral hydrate in the proportion of 1 part chloral hydrate to, at least, 0.8 part by weight of glycine.

3. The tablet according to claim 2 in which said coating comprises a plurality of layers and at least one said layer, not adjacent said core, includes a barbiturate chosen from the group consisting of secobarbital and butabarbital.

4. A stable non-hygroscopic chloral hydrate composition comprising one part by weight of chloral hydrate and approximately 1.37 parts by weight of glycine.

5. A stable, solid dosage chloral hydrate composition comprising one part by weight of chloral hydrate and at least 0.8 part by weight of glycine.

6. The tablet according to claim 2 in which said coating includes a plurality of layers at least one of which is spaced from said core and includes a second therapeutic substance.

7. A non-hygroscopic chloral hydrate composition adapted for use as material for making a stable storable tablet, said composition comprising a dried product of an intimate mixture of powdered chloral hydrate and powdered glycine.

8. The process of preparing a stable chloral hydrate composition of chloral hydrate and glycine wherein said chloral hydrate and glycine are mixed, moistened by a liquid vehicle, and the composition is then dried at a temperature substantially below the boiling point of chloral hydrate.

9. The process according to claim 8 in which said composition is dried at a temperature of approximately 80 F.

References Cited by the Examiner UNITED STATES PATENTS 6 OTHER REFERENCES Cooper: J. Am. Pharm. Assoc., Sc. Ed., vol. 46, No. 9, September 1957, p. 521.

Groves: J. Am. Vet. Med. Assoc., 119: 892, July 1, 1951, pages 50-54.

Jenkins: The Art of Compounding, Blakiston Division, 1957, McGraw-Hill, pp. 93-99.

Remingtons Practice of Pharmacy, February 1956, The

UI'SUIII 167-52 Mack Pub. Co., Easton, Pa., p. 373-379.

Sahyun 167 10 Remington: Practice of Pharmacy, 1956, page 76 Endicott 167-82 Mack Pub. Co.

Klioze 167-82 Wood: Tablet Manufacture, J. B. Lipincott Co., Phila- Cooper 16782 delphia, Pa., 1904, p. 25.

Brown 167-82 Bardani 1 7 82 15 JULIAN S. LEVITT, Primary Examiner.

Millard et a1 16782 FRANK CACCIAPAGLIA, JR., MORRIS O. WOLK, Endicott 167-82 IRVING MARCUS, LEWIS GO'ITS, Examiners. 

1. THE PROCESS OF PREPARING A STABLE, SOLID DOSAGE CHLORAL HYDRATE TABLET COMPRISING THE STEPS OF MIXING CHLORAL HYDRATE AND GLYCINE, IN THE PROPORTION OF AT LEAST 0.8 PART BY WEIGHT OF GLYCINE TO 1 PART BY WEIGHT OF CHLORAL HYDRATE, MOISTENED BY THE PRESENCE OF A LIQUID VEHICLE, GRANULATING THE MIXTURE, DRYING THE MASS AT A TEMPERATURE SUBSTANTIALLY BELOW THE BOILING POINT OF CHLORAL HYDRATE, AND COMAPRESSING THE MASS INTO TABLETS PREDETERMINED SIZE. 